tbuckley/cabot-search huggingface dataset:
Abstract 191: Establishment and characterization of patient-derived cancer cell models for pharmaceutical drug screening
Authors: Gareth J. Griffiths, Abbie Dodd, Olivia Nee, Tilly Thuringer, Subir Singh, Rachel Howard-Jones, Yuen Ngan Fan, Albert Bezman, Rachel Bell, Ido Sloma, Chris Noakes, Dominic I. James
Journal: Cancer Research (2022)

Abstract Patient-derived cell (PDC) models are a tool that bridge the gap between conventional cancer lines that do not faithfully replicate clinical responses and costly and time-consuming patient derived xenograft (PDX) models. Imagen Therapeutics is establishing the world’s largest biobank of PDC models for both patient diagnostic (PredictRx) and biopharma drug development (PredictTx) studies that show a high degree of correlation between PDC and patient drug response. Through our research, we have established unique culture conditions that specifically select for cancer stem cells, and these have been characterized using both 2-D and 3-D short-term high content image (HCI)-based analysis. To better understand the genomic and phenotypic profiles of these models we analyzed Next Generation Sequencing data and phenotypic cell killing using a panel of FDA-approved agents. Our results showed that mRNA expression of several known cancer stem cell markers were upregulated in our PDCs in addition to multidrug resistance (MDR) genes. Drug resistance in the phenotypic assay was then correlated with stemness and MDR expression profiles. Finally, sequential PDCs (models developed from same patient at different stages in disease progression), in addition to PDCs developed from the same patient at multiple lesion sites, were compared in terms of genomic sequencing and drug responses. Together our data supports the premise that PDCs recapitulate the cancer stem cell population and are a useful platform with which to interrogate drug responses in a variety of different cancer types. Citation Format: Gareth J. Griffiths, Abbie Dodd, Olivia Nee, Tilly Thuringer, Subir Singh, Rachel Howard-Jones, Yuen Ngan Fan, Albert Bezman, Rachel Bell, Ido Sloma, Chris Noakes, Dominic I. James. Establishment and characterization of patient-derived cancer cell models for pharmaceutical drug screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 191.
Abstract 6191: A novel anti-IL33 antibody that neutralized Th1-type and Th2-type pro-inflammation responses induced by IL-33/ST2 axis pathway
Authors: Xuesai Zhang, Qingrou Li, Cui Liu, Le Zhao, Lujie Wang, Lan Deng, Wei Xu, Hongli song, Zhenping Zhu, Haomin Huang
Journal: Cancer Research (2022)

Abstract IL-33, the ligand for ST2, is a member of IL-1 family. IL-33 was described to activate many immune cell types involved in type-2 immunity and allergic inflammation. Here we describe a novel anti-IL33 humanized monoclonal antibody, SSGJ-621, which bound IL-33 with high affinity and blocked the interaction between IL-33 and ST2. Our study has shown that SSGJ-621 was capable of effectively neutralizing IL-33-induced IL-6 secretion from HUVECs and IL-33-dependent IFNγ production in PBMCs and NK cells, suggesting a role that IL-33 might be involved in Th1-type of immunity. In addition, SSGJ-621 also exhibited potent inhibitory effects on IL-33 induced IL-5 and IL-13 production in KU812 cells. In vivo study demonstrated that SSGJ-621 can inhibit the activation of splenocytes in spleen and the production of eosinophils and IL-5 in peripheral blood. Thereby, our results highlight the dual functions of IL-33 in promoting Th1 and Th2 immune responses and SSGJ-621 has potentials to treat not only chronic inflammatory diseases induced by IL-33, but also cancers by favoring Th1 antitumor immunity in the tumor microenvironment. Citation Format: Xuesai Zhang, Qingrou Li, Cui Liu, Le Zhao, Lujie Wang, Lan Deng, Wei Xu, Hongli song, Zhenping Zhu, Haomin Huang. A novel anti-IL33 antibody that neutralized Th1-type and Th2-type pro-inflammation responses induced by IL-33/ST2 axis pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6191.
Abstract 1611: Temporal recapitulation of genome instability in an iPSC model of osteosarcoma
Authors: Kelsie Lynn Becklin, Rebecca Madden, Lauren Mills, Nicole Thue, Nathan Carroll, Anthony DeFeo, Branden Moriarity, Beau Webber
Journal: Cancer Research (2022)

Abstract Osteosarcoma (OS) is characterized by widespread genomic instability, with cellular transformation associated with extensive structural (SV) and copy number variation (CNV). TP53 and RB1 mutations contribute to the initiation and maintenance of genome instability, which serves as a key driver of relapse. Significant effort has been made to model OS genome instability; however, current models have limited capacity to recapitulate genomic instability in real time. To model OS initiation and development, TP53 and RB1 mutations were installed in human iPSC using CRISPR/Cas9, followed by differentiation to mesenchymal (iMSC) and osteoblast (iOB) lineages in vitro. Functional assays of transformation were then conducted at intermediate stages of development for each genotype. Compared to isogenic WT controls, TP53-/- and TP53-/-/RB1-/- iOB exhibited increased proliferation, whereas anchorage independent growth was only observed in TP53-/-/RB1-/- iOB. Overexpression of cMYC and hRAS significantly increased the magnitude of these results in iOB. In contrast to iOB, TP53-/-/RB1-/- iMSC did not form colonies without cMYC and hRAS overexpression. To evaluate this phenomenon in vivo, iMSC and iOB were injected into the calcaneal bone of immunodeficient mice. Consistent with our in vitro observations, TP53-/-/RB1-/- and TP53-/-/RB1-/-+cMYC/hRAS iOB, and TP53-/-/RB1-/-+cMYC/hRAS iMSC gave rise to tumors. Histological evaluation of MSC-derived tumors revealed a largely undifferentiated pleomorphic phenotype, with a progressive increase in complexity in tumors derived from later stage iOB. Global gene expression signatures of xenografted tumors bore a striking similarity to OS patient samples compared to other pediatric tumors. In follow-on experiments, a progressive increase in cytogenetic abnormalities were observed in mutant but not WT iMSC, which became more pronounced in mutant iOB and correlated with a transformed phenotype. We are currently evaluating the temporal kinetics of this process, including through the use of low-coverage whole genome sequencing to elucidate the existence of recurrent patterns. These data highlight the utility of our iPSC approach as a novel model of OS, allowing for the first time the ability to study the evolution of genome instability in real time. We envision that this approach may uncover heretofore undiscovered common patterns underlying the seemingly chaotic nature of OS genomes, providing new opportunities for therapeutic intervention. Citation Format: Kelsie Lynn Becklin, Rebecca Madden, Lauren Mills, Nicole Thue, Nathan Carroll, Anthony DeFeo, Branden Moriarity, Beau Webber. Temporal recapitulation of genome instability in an iPSC model of osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1611.
Abstract 3019: The epigenetic factor KDM2B alters the serine-glycine synthesis pathway and the one-carbon metabolism (SGOC) in triple-negative breast cancer
Authors: Evangelia Chavdoula, Vollter Anastas, Alessandro La Ferlita, Julian Aldana, Anuvrat Sircar, Michael A. Freitas, Lalit Sehgal, Philip N. Tsichlis
Journal: Cancer Research (2022)

Abstract Epigenetic and metabolic alterations in cancer cells are intertwined. The concentration of metabolites can influence the activity of chromatin modifiers, which in turn can act as metabolic sensors that translate changes in cellular metabolism to transcriptional reprogramming. In the present study, we investigated the role of histone demethylase KDM2B in the metabolic reprogramming of the triple-negative breast cancer (TNBC), in which KDM2B is selectively expressed at high levels. Knockdown of KDM2B in TNBC cell lines reduced their proliferation rate and tumor growth in vivo. Transcriptomic, proteomic, and metabolomic profiling demonstrated that the Serine-Glycine pathway and One Carbon metabolism (SGOC) and other amino acid biosynthetic and catabolic processes are downregulated by the knockdown of KDM2B. Additionally, we see reduction of metabolites produced via these pathways (purines, pyrimidines, formate, glutathione and NADPH). Importantly, the expression of the enzymes involved in the SGOC metabolic pathway (e.g. PHGDH, PSAT1, PSPH, SHMT2, MTHFD1L, MTHFD2 and DHFR) depends on c-MYC, NRF2, and ATF4 which our data show that they are under the positive regulatory control of KDM2B. The epistatic relationship between these factors, with the expression of the enzymes of the SGOC pathway and the effects of the KDM2B knockdown on chromatin occupancy and accessibility of the promoters of these factors is in progress and will be presented. Analysis of TCGA data showed positive and statistically significant correlations between KDM2B and the SGOC gene signature in TNBC patients. In addition, the metabolic pathway signature that distinguishes control and shKDM2B-transduced cells corresponds to the metabolic signature of a subset of TNBCs, which have been reported to carry poor prognosis. The present study highlights the role of the epigenetic factor KDM2B as an upstream regulator of the metabolic reprogramming of TNBC. Citation Format: Evangelia Chavdoula, Vollter Anastas, Alessandro La Ferlita, Julian Aldana, Anuvrat Sircar, Michael A. Freitas, Lalit Sehgal, Philip N. Tsichlis. The epigenetic factor KDM2B alters the serine-glycine synthesis pathway and the one-carbon metabolism (SGOC) in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3019.
An antigen-strengthened dye-modified fully-human-nanobody-based immunoprobe for second near infrared bioimaging of metastatic tumors
Authors: Yibing Shi, Huifang Wu, Weiqiang Hu, Yujia Jin, Mengya Kong, Yulu Wang, Binfan Chen, Quanxiao Li, Keke Huang, Zhenlin Yang, Fuyou Li, Yanling Wu, Tianlei Ying
Journal: Biomaterials (2022)
Antithrombotic Therapy in Atrial Fibrillation and Coronary Artery Disease
Authors: Ying X. Gue, Diana A. Gorog, Gregory Y. H. Lip
Journal: JAMA Cardiology (2022)

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Abstract 2711: Repurposing CAR targets in solid tumors from pan-cancer single-cell RNA-seq data
Authors: Sanna Madan, Alejandro Schäffer, Eytan Ruppin
Journal: Cancer Research (2022)

Abstract Chimeric antigen receptor (CAR) T cell therapy is a powerful and promising tool for unleashing lasting antitumor immunity, which is currently studied in numerous blood and solid cancers. Here, mining single cell transcriptomics datasets of solid tumors, we survey many existing CAR targets, aiming to identify new solid tumor types in which these targets are differentially expressed in tumor cells and not on non-tumor cells within the tumor microenvironment, thus providing new repurposing opportunities. Quite surprisingly, we find that many existing solid cancer CAR targets have a better discriminatory power in uncharted cancer types than in the ones they have been developed or being tested for. Furthermore, we show that several existing liquid cancer CAR targets may also hold promise in specific solid tumors. Taken together, this analysis uncovers a large potential of repurposing current CARs that is currently yet untapped. Citation Format: Sanna Madan, Alejandro Schäffer, Eytan Ruppin. Repurposing CAR targets in solid tumors from pan-cancer single-cell RNA-seq data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2711.
Abstract 5120: Deciphering melanoma CTC signatures leading to immune escape and brain metastasis: The first MRI CTC xenograft model
Authors: Tetiana Bowley, Dario Marchetti
Journal: Cancer Research (2022)

Abstract Melanoma brain metastasis (MBM) is a devastating disease which is diagnosed in up to 60% of melanoma patients and 80% of patients at autopsy. While microarray studies identified many genes differentially expressed between MBM and extracranial metastasis, magnetic resonance imaging (MRI) is the established technology to evaluate clinical MBM. Circulating Tumor Cells (CTCs) are “seeds” of fatal metastasis and smallest functional units of cancer. Defining mechanisms which regulate the spatial and temporal competence of patient-isolated CTCs driving MBM thus presents the opportunity to suppress its occurrence. Hypothesis is that MRI has fundamental translational relevance to validate preclinical CTC models and that MBM onset depends upon the absence or presence of human immune system cells (Hu-mice), and mice gender and age. We isolated CTCs from blood of primary/metastatic melanoma patients, and confirmed CTC detection by CellSearch࣪, Parsortix࣪, high-definition microscopy and RNA-Seq profiling. Second, we injected melanoma CTCs in immunodeficient but also immunocompetent xenografts (NBSGW female/male mice generated by multiple donors CD34+ cells), and assessed tumor progression by IVIS and MRI with parallel monitoring of CTC gene-specific transcriptional activation. Third, we discovered specific differences in number of CTCs/CTC clustering patterns and CTC signatures which were dependent upon MBM status. Quantitation of melanoma CTC-derived signatures enabled serial noninvasive monitoring of tumor burden. Lastly, we found that these differences and the occurrence, severity and spatial distribution of MBM highly depended from gender, age, and immunocompetency status of injected animals. Thus, by reporting the first MRI CTC xenograft model, its use for melanoma CTC interrogation can provide a platform for early monitoring of response to immunotherapeutic and/or targeted interventions in melanoma, and contribute to rational therapy applications, notably for MBM prediction or prevention. Citation Format: Tetiana Bowley, Dario Marchetti. Deciphering melanoma CTC signatures leading to immune escape and brain metastasis: The first MRI CTC xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5120.
Abstract 3452: Morphological phenotyping of organotropic brain- and bone-seeking triple negative metastatic breast tumor cells
Authors: Ariana Joy L. DeCastro, Marina Pranda, Kelsey Gray, John Merlo-Coyne, Nathaniel Girma, Madelyn Hurwitz, Yuji Zhang, Kimberly Stroka
Journal: Cancer Research (2022)

Abstract Triple negative breast cancer (TNBC) follows a non-random pattern of metastasis to the bone and brain tissue. Prior work has found that brain-seeking breast tumor cells display altered proteomic profiles, leading to alterations in pathways related to cell signaling, cell cycle, metabolism, and extracellular matrix remodeling. Given the unique microenvironmental characteristics of brain and bone tissue, we hypothesized that brain- or bone-seeking TNBC cells may have altered morphologic or migratory phenotypes from each other, or from the parental TNBC cells, as a function of the biochemical or mechanical microenvironment. In this study, we utilized TNBC cells (MDA-MB-231) that were conditioned to metastasize solely to brain (MDA-BR) or bone (MDA-BO) tissue. We quantified characteristics such as cell morphology, migration, and stiffness in response to cues that partially mimic their final metastatic niche. We have shown that MDA-BO cells have a distinct protrusive morphology not found in MDA-P or MDA-BR. Further, MDA-BO cells migrate over a larger area when on a collagen I (abundant in bone tissue) substrate when compared to fibronectin (abundant in brain tissue). However, migration in highly confined environments was similar across the cell types. Modest differences were found in the stiffness of MDA-BR and MDA-BO cells plated on collagen I vs. fibronectin-coated surfaces. Lastly, MDA-BO cells were found to have larger focal adhesion area and density in comparison with the other two cell types. These results initiate a quantitative profile of mechanobiological phenotypes in TNBC, with future impacts in helping to predict metastatic propensities to organ-specific sites in a clinical setting. Citation Format: Ariana Joy L. DeCastro, Marina Pranda, Kelsey Gray, John Merlo-Coyne, Nathaniel Girma, Madelyn Hurwitz, Yuji Zhang, Kimberly Stroka. Morphological phenotyping of organotropic brain- and bone-seeking triple negative metastatic breast tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3452.
Transplantation Tolerance through Hematopoietic Chimerism
Authors: Thomas R. Spitzer, David H. Sachs
Journal: New England Journal of Medicine (2022)

Stunning advances in human transplantation have been tempered by the immunologic consequences of histoincompatibility between donor and recipient — namely, allograft rejection after solid-organ transplantation and graft-versus-host disease (GVHD) after hematopoietic stem-cell (bone marrow) transplantation (HSCT). The separation of GVHD from the graft-versus-tumor effect and the induction of functional immune tolerance, defined by the absence of a destructive immune response in the absence of systemic immunosuppression, have been considered the "Holy Grail" of HSCT and solid-organ transplantation, respectively. Freedom from immunosuppression after organ transplantation has a tremendous potential upside, since lifelong immunosuppressive therapy is sometimes complicated by debilitating or life-threatening . . .
Abstract 5589: BYON4228 is a pan-allelic SIRPα antibody that potentiates killing of antibody-opsonized tumor cells and lacks binding to T cells
Authors: Mary van Helden, Seline Zwarthoff, Hugo Olsman, Marc Paradé, Ellen Mattaar, Karin de Laat, Imke Lodewijks, Paul Boersema, Lilian Driessen-Engels, Jorien Sanderink, Wendy Kappers, Diels van den Dobbelsteen, Ruud Ubink, Roel Arends, Gerard Rouwendal, Gijs Verheijden, Miranda van der Lee, Wim Dokter, Timo Van den Berg
Journal: Cancer Research (2022)

Abstract Preclinical data have established CD47-SIRPα interactions as a myeloid immune checkpoint in cancer, which is corroborated by preliminary evidence from the first clinical studies with CD47 blockers. However, the ubiquitously expressed CD47 mediates functional interactions with other ligands as well, and therefore targeting of the primarily myeloid cell-restricted inhibitory immunoreceptor SIRPα may represent a better strategy. Here, we present preclinical results on a novel clinical candidate, BYON4228. BYON4228 is an antibody directed against SIRPα and recognizes both of the common allelic variants of human SIRPα which maximizes its potential clinical application in the broad human population. Notably, in contrast to several other anti-SIRPα antibodies in development, BYON4228 does not recognize the closely related T cell-expressed SIRPγ that has been reported to mediate interactions with CD47 as well, which are known to be instrumental in T cell extravasation and activation. BYON4228 binds to the N-terminal part of SIRPα and its epitope overlaps with the CD47-binding site. BYON4228 therefore prevents binding of CD47 to SIRPα and thus blocks inhibitory signaling through the CD47-SIRPα axis. Functional studies show that BYON4228 potentiates both macrophage- and neutrophil-mediated elimination of hematologic and solid cancer cells in vitro in the presence of several different tumor targeting antibodies like trastuzumab, rituximab, daratumumab and cetuximab, illustrating the broad potential clinical benefit and application of BYON4228. Single intravenous infusion of up to 100 mg/kg BYON4228 to male and female cynomolgus monkeys was well tolerated and did not elicit any adverse effects. Collectively, this defines BYON4228 as a pan-allelic anti-SIRPα antibody without T cell SIRPγ recognition that promotes the destruction of antibody-opsonized cancer cells. Clinical studies are planned to start in 2022. Citation Format: Mary van Helden, Seline Zwarthoff, Hugo Olsman, Marc Paradé, Ellen Mattaar, Karin de Laat, Imke Lodewijks, Paul Boersema, Lilian Driessen-Engels, Jorien Sanderink, Wendy Kappers, Diels van den Dobbelsteen, Ruud Ubink, Roel Arends, Gerard Rouwendal, Gijs Verheijden, Miranda van der Lee, Wim Dokter, Timo Van den Berg. BYON4228 is a pan-allelic SIRPα antibody that potentiates killing of antibody-opsonized tumor cells and lacks binding to T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5589.